I. Field of The Invention
This invention relates to a method of preparing a controlled long-acting release pharmaceutical formulation containing an active therapeutic agent and a carrier base material in unit dosage form. More specifically, this invention relates to a method of preparing batches of unit doses of oral tablets, lozenges, suppositories and the like, of a controlled long-acting pharmaceutical formulation containing an active therapeutic agent and a carrier base material, wherein each of the unit doses has a substantially comparable and uniform bioavailability characteristic when consumed. The invention also relates to the improved unit dosage forms prepared by the method of the invention.
This invention relates broadly to controlled long-acting pharmaceutical formulations containing a variety of active therapeutic agents and carrier base materials consisting of at least one cellulose ether. The cellulose ethers typically used in the methods and compositions of the invention are hydroxyalkyl celluloses or hydroxyalkyl alkylcellulose materials such as hydroxypropyl methylcellulose and similar analogs.
Long-acting products are widely marketed in the pharmaceutical field and are now a significant factor in the administration of a variety of active pharmaceutical agents. The advantages of such long-acting or sustained release products are now well understood and a very substantial industry has developed around these products. Sustained release products permit various medications to be administered for uniform and continuous release over a prolonged period of time thereby achieving a particular blood level of active ingredient for whatever time is thought to be advantageous to the patient. Such administration obviates the necessity for requiring frequent administration of active ingredient and avoids the problems inherent in insuring timely and repetitive consumption of pharmaceutical product by the patient. It is possible to achieve stable blood levels of a variety of active therapeutic agents and thereby control a variety of physiological conditions. It also reduces or possibly eliminates toxic or side effects which are caused by frequent administration of active ingredients through the peaks and valleys of blood levels caused by multiple ingestion of medication.
II. Description of The Prior Art
The use of cellulosic derivatives, more particularly cellulose ethers such as hydroxypropyl methylcellulose as a carrier in long-acting or sustained release pharmaceutical formulations is well known. A variety of commercial forms of cellulosic ethers are commercially available and these include methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, carboxymethyl cellulose and hydroxypropyl cellulose, and derivatives, among others. These cellulose ethers are each available in a range of molecular weights and viscosities and under a variety of trade names.
Hydroxypropyl methylcellulose is a particularly preferred cellulose ether for the sustained release compositions of the invention and it is available from Dow Chemical Company under the Methocel trademark. The several hydroxypropyl methylcellulose products have varying methoxyl and hydroxypropoxyl contents as well as different molecular weights. Typically, the methoxyl content ranges from 16.5 to 30 weight percent and the hydroxypropyl content ranges from 4 to 32 weight percent. The viscosities of the several grades of hydroxypropyl methylcellulose, as calculated based on the viscosity of a 2% aqueous solution at 20.degree. C., range from 5 cps to 100,000 cps. Typically the higher viscosity grade materials dissolve more slowly and can be used in lesser amounts than comparable materials having lesser viscosities.
The prior art dates back to about the 1960's. Christiansen et. al., U.S. Pat. No. 3,065,143, disclosed the use of hydroxypropyl methylcellulose in sustained release tablets. Lowey et al., in U.S. Pat. No. 3,870,790, disclosed processes for mixing an active therapeutic ingredient with premoisturized hydroxypropyl methylcellulose which could also optionally be mixed with ethylcellulose. The sustained release properties of the resulting mixture could be controlled by the moisture content of the carrier material which was in turn set in a moisturizing process wherein the carrier material was subjected to elevated temperature and humidity conditions.
Lowey, U.S. Pat. No. 4,259,314, disclosed sustained release products which consisted of mixtures of hydroxypropyl methylcellulose having a viscosity of from 50 to 4,000 cps and hydroxypropyl cellulose. These mixtures, particularly when dried to less than one percent moisture, were advantageously used with hygroscopic active agents.
Other workers, including Schor et al., U.S. Pat. No. 4,389,393, have disclosed sustained release compositions wherein the carrier base material is selected from certain preferred forms of hydroxypropyl methylcellulose having certain defined viscosities, methoxyl contents, hydroxypropyl contents and number average molecular weights.
In preparing tablets according to prior art methods, the carrier base material is first prepared. A mixture of cellulosic components can be employed and, if deemed desirable, the carrier base mixture can be treated by humidification or other process steps. The active ingredient is then added to the carrier base material and thoroughly intermixed with the base to form a uniform mixture. The mixture of active ingredient and carrier is removed to the hopper of a tableting machine. Such machines are well known in the art and may have variable size punches preset and are adjustable to control the compression of the tablet. For example, punches and dies from 5/32 to 3/4 inches can be employed and the tableting machines may be adjusted to vary the compressive pressure from 6 to 14 kg/cm.sup.2. These variables and the control of them are well understood in the prior art and it is recognized that sustained release properties are a function both of the size of the tablet and the compression to which it is subjected. Thus 1/4 to 15 grain tablets can be produced according to prior art methods.
It is of considerable importance in the administration of controlled, long-acting release pharmaceutical tablets, lozenges and the like, that the rate of release of the active agent from the tablet be consistent and uniform among tablets prepared in a given manufacturing batch and among tablets prepared at different times in different manufacturing batches. It is critical, both from the standpoint of the safety of the administration of the therapeutic agent as well as the reliability thereof, that the bioavailability characteristic of the tablets prepared be substantially uniform and comparable. In the absence of such reliability, the dangers to a patient are significant because active ingredient may be release at faster or slower rates than are assumed. For example, where nitroglycerin is being administered to angina patients via oral or buccal tablets, such variation in release may be life-threatening. The problem of noncomparable release rates among presumably identical tablets is particularly exacerbated where those tablets are of the "one-a-day" type and where the patient is relying upon a uniform and comparable release day after day from these tablets.
A problem that has confronted the art is that of preparing multiple long-acting tablets wherein each tablet releases the active ingredient uniformly and comparably. To achieve the proper bioavailability of active ingredient over time from tablet to tablet and from batch to batch requires not only that the same amount of active ingredient be incorporated within each tablet but that the active ingredient be thoroughly mixed and bonded to the cellulosic carrier base material in the same manner so that release is not faster from one tablet than from another.